The deregulation of Signal Transducers and Activators of Transcription (STAT) pathways occurs during development of many types of tumors. Among STAT family members, aberrant activation of STAT3 is most frequent in almost all blood malignancies and solid tumors, including lymphomas and leukemias, breast, prostate, lung, head and neck, brain and colon cancers. Thus, the STAT family of proteins, particularly STAT3, is a promising target for the development of novel anticancer drugs.
STAT3 is believed to be activated in the cytoplasm by tyrosine phosphorylation in response to stimulation with growth factors and cytokines. Phosphorylation triggers dimerization and translocation to the nucleus followed by binding to STAT-specific DNA-response elements in the promoters of target genes. Dephosphorylated STAT3 is released from DNA and returns to the cytoplasm. Among the known major STAT3 target genes are those that control cell cycle progression and growth, survival, angiogenesis, motility, and differentiation. STAT3 activation is normally transient and tightly regulated, as is the expression of its target genes. Constitutively active STAT3 induces deleteriously prolonged activation of some target genes, thus contributing to tumor growth and progression.
Most currently available STAT inhibitors target the abnormally activated kinases upstream of STAT. However, direct inhibitors of STAT offer greater selectivity. Thus, there remains a desire for additional STAT inhibitors, especially direct inhibitors of STAT.